22q13 deletion syndrome,
known as Phelan–McDermid syndrome (PMS), is a genetic disorder caused by deletions or rearrangements on the q terminal end (long arm) of chromosome 22. Any abnormal genetic variation in the q13 region that presents with significant manifestations (phenotype) typical of a terminal deletion may be diagnosed as 22q13 deletion syndrome. There is disagreement among researchers as to the exact definition of 22q13 deletion syndrome.[1] The Developmental Synaptopathies Consortium defines PMS as being caused by SHANK3 mutations, a definition that appears to exclude terminal deletions.[2] The requirement to include SHANK3 in the definition is supported by many but not by those who first described 22q13 deletion syndrome.[3]
Prototypical terminal deletion of 22q13 can be uncovered by karyotype analysis, but many terminal and interstitial deletions are too small. The availability of DNA microarray technology for revealing multiple genetic problems simultaneously has been the diagnostic tool of choice. The falling cost for the whole exome sequencing and, eventually, whole genome sequencing, may replace DNA microarray technology for candidate evaluation. However, fluorescence in situ hybridization (FISH) tests remain valuable for diagnosing cases of mosaicism (mosaic genetics) and chromosomal rearrangements (e.g., ring chromosome, unbalanced chromosomal translocation). Although early researchers sought a monogenic (single gene genetic disorder) explanation, recent studies have not supported that hypothesis (see Etiology).
Affected individuals present with a broad array of medical and behavioral manifestations (tables 1 and 2).[4][5][6][7] Patients are consistently characterized by global developmental delay, intellectual disability, speech abnormalities, ASD-like behaviors, hypotonia and mild dysmorphic features.[4][6][7][8][9][10][11][12][13][14][15][16] Table 1 summarizes the dysmorphic and medical conditions that have been reported in individuals with PMS. Table 2 summarizes the psychiatric and neurological symptoms associated with PMS. Most of the studies include small samples or relied on parental report or medical record review to collect information, which can account in part for the variability in the presentation of some of the presenting features. Larger prospective studies are needed to further characterize the phenotype.
Table 1: dysmorphic features and medical comorbid conditions that have been reported in individuals with Phelan–McDermid syndrome
Various deletions affect the terminal region of the long arm of chromosome 22 (the paternal chromosome in 75% of cases,[citation needed]) from 22q13.3 to 22qter. Although the deletion is most typically a result of a de novo mutation, there is an inherited form resulting from familial chromosomal translocations involving the 22 chromosome. In the de novo form, the size of the terminal deletion is variable and can go from 130 Kb (130,000 base pairs) to 9 Mb. Deletions smaller than 1 Mb are very rare (about 3%). The remaining 97% of terminal deletions impact about 30 to 190 genes (see list, below). At one time it was thought that deletion size was not related to the core clinical features.[17] That observation lead to an emphasis on the SHANK3 gene, which resides close to the terminal end of chromosome 22. Interest in SHANK3 grew as it became associated with autism spectrum disorder (ASD) and schizophrenia.[18] Since then, twelve other genes on 22q13 (MAPK8IP2,[19]CHKB,[20]SCO2,[21]SBF1,[22]PLXNB2,[23]MAPK12,[24]PANX2,[25]BRD1,[26]CELSR1,[27]WNT7B,[28]TCF20[29]) have been associated with autism spectrum disorder and/or schizophrenia (see references below). Some mutations of SHANK3 mimic 22q13 deletion syndrome, but SHANK3 mutations and microdeletions have quite variable impact.[citation needed]
Some of the core features of 22q13 deletion syndrome are dependent upon deletion size, and do not depend on the loss of SHANK3.[30][31][32] As noted above, the distal 1 Mb of 22q is a gene rich region. There are too few clinical cases to statistically measure the relationship between deletion size and phenotype in this region. SHANK3 is also adjacent to a gene cluster (ARSA and MAPK8IP2)[33] that has a high probability of contributing to ASD,[34] suggesting the effects of SHANK3 deletion may be indistinguishable from other genetic losses. A landmark study of induced pluripotent stem cell neurons cultured from patients with 22q13 deletion syndrome shows that restoration of the SHANK3 protein produces a significant, but incomplete rescue of membrane receptors, supporting both a substantial role for SHANK3 and an additional role for other genes in the distal 1 Mb of chromosome 22.[35]
There is an interest in the impact of MAPK8IP2 (also called IB2) in 22q13 deletion syndrome.[36] MAPK8IP2 is especially interesting because it regulates the balance between NMDA receptors and AMPA receptors.[37] The genes SULT4A1[38] and PARVB[39] may cause 22q13 deletion syndrome in cases of more proximal interstitial and large terminal deletions.[32] There are about 187 protein coding genes in the 22q13 region.[40] A group of genes (MPPED1,[41]CYB5R3,[42]FBLN1,[43]NUP50,[44]C22ORF9,[45]KIAA1644,[46]PARVB,[39] TRMU,[47]WNT7B[48] and ATXN10[49]), as well as microRNAs may all contribute to loss of language, a feature that varies notably with deletion size.[50] The same study found that macrocephaly seen in 22q13 deletion syndrome patients may be associated with WNT7B. FBLN1 is responsible for synpolydactyly as well as its contribution to the neurological manifestations (OMIM 608180).
RABL2B
ACR
SHANK3
ARSA
MAPK8IP2
CHKB
CPT1B
SYCE3
KLHDC7B
ODF3B
TYMP
SCO2
NCAPH2
LMF2
MIOX
ADM2
SBF1
PPP6R2
DENND6B
PLXNB2
MAPK11
MAPK12
HDAC10
TUBGCP6
SELO
TRABD
PANX2
MOV10L1
MLC1
IL17REL
PIM3
CRELD2
ALG12
ZBED4
BRD1
FAM19A5
FLJ32756
TBC1D22A
CERK
GRAMD4
CELSR1
TRMU
BC069212
GTSE1
TTC38
PKDREJ
CDPF1
PPARA
WNT7B
ATXN10
FBLN1
RIBC2
SMC1B
FAM118A
UPK3A
KIAA0930
NUP50
PHF21B
PRR5-ARHGAP8
LDOC1L
KIAA1644
PARVG
TRNA_SeC
PARVB
SAMM50
PNPLA3
PNPLA5
SULT4A1
EFCAB6
MPPED1
SCUBE1
TTLL12
TSPO
MCAT
BIK
TTLL1
PACSIN2
ARFGAP3
A4GALT
ATP5L2
DL490307
CYB5R3
RNU12
POLDIP3
SERHL2
RRP7A
NFAM1
TCF20
CYP2D6
NDUFA6
SMDT1
FAM109B
NAGA
WBP2NL
CENPM
TNFRSF13C
SHISA8
SREBF2
CCDC134
MEI1
C22orf46
NHP2L1
XRCC6
DESI1
PMM1
CSDC2
POLR3H
ACO2
PHF5A
TOB2
TEF
ZC3H7B
RANGAP1
CHADL
L3MBTL2
EP300
RBX1
DNAJB7
XPNPEP3
ST13
SLC25A17
MCHR1
MKL1
SGSM3
ADSL
TNRC6B
FAM83F
GRAP2
ENTHD1
CACNA1I
RPS19BP1
ATF4
SMCR7L
MGAT3
TAB1
SNORD43
RPL3
PDGFB
CBX7
APOBEC3H
APOBEC3F
APOBEC3D
APOBEC3C
APOBEC3B
CBX6
NPTXR
DNAL4
SUN2
GTPBP1
JOSD1
TOMM22
CBY1
FAM227A
DMC1
DDX17
KDELR3
KCNJ4
CSNK1E
TMEM184B
MAFF
MAFF
PLA2G6
BAIAP2L2
SLC16A8
PICK1
SOX10
POLR2F
C22orf23
MICALL1
EIF3L
ANKRD54
GALR3
GCAT
H1F0
TRIOBP
NOL12
LGALS1
SH3BP1
GGA1
LGALS2
CDC42EP1
CARD10
MFNG
ELFN2
CYTH4
Table of protein coding genes involved in 22q13 deletion syndrome (based on Human Genome Browser – hg38 assembly [51]). Underline identifies 13 genes that are associated with autism.[52][53][54][55] Bold identifies genes associated with hypotonia (based on Human Phenotype Browser [56] search for 'hypotonia' and the OMIM database [57]).
Genetic testing is necessary to confirm the diagnosis of PMS. A prototypical terminal deletion of 22q13 can be uncovered by karyotype analysis, but many terminal and interstitial deletions are too small to detect with this method.[8][58] Chromosomal microarray should be ordered in children with suspected developmental delays or ASD.[59][60] Most cases will be identified by microarray; however, small variations in genes might be missed. The falling cost for whole exome sequencing may replace DNA microarray technology for candidate gene evaluation. Biological parents should be tested with fluorescence in situ hybridization (FISH) to rule out balanced translocations or inversions. Balanced translocation in a parent increases the risk for recurrence and heritability within families (figure 3).[61]
Clinical genetic evaluations and dysmorphology exams should be done to evaluate growth, pubertal development, dysmorphic features (table 1) and screen for organ defects (table 2)
All patients should undergo comprehensive developmental, cognitive and behavioral assessments by clinicians with experience in developmental disorders. Cognitive evaluation should be tailored for individuals with significant language and developmental delays.[8] All patients should be referred for specialized speech/language, occupational and physical therapy evaluations.
Individuals with PMS should be followed by a pediatric neurologist regularly to monitor motor development, coordination, and gait, as well as conditions that might be associated with hypotonia.[9] Head circumference should be performed routinely up until 36 months. Given the high rate of seizure disorders (up to 41% of patients) reported in the literature in patients with PMS and its overall negative impact on development, an overnight video EEG should be considered early to rule out seizure activity. In addition, a baseline structural brain MRI should be considered to rule out the presence of structural abnormalities.[5]
All patients should have a baseline renal and bladder ultrasonography and a voiding cystourethrogram should be considered to rule out structural and functional abnormalities. Renal abnormalities are reported in up to 38% of patients with PMS.[62][63] Vesicouretral reflux, hydronephrosis, renal agenesis, dysplastic kidney, polycystic kidney and recurrent urinary tract infections have all been reported in patients with PMS.
Congenital heart defects (CHD) are reported in samples of children with PMS with varying frequency (up to 25%)(29,36). The most common CHD include tricuspid valve regurgitation, atrial septal defects and patent ductus arteriosus. Cardiac evaluation, including echocardiography and electrocardiogram, should be considered.[8]
Gastrointestinal symptoms are common in individuals with PMS. Gastroesophageal reflux, constipation, diarrhea and cyclic vomiting are frequently described.[64]
Table 3: Clinical Assessment Recommendations in Phelan–McDermid Syndrome
Medical Specialty
Assessment Recommended
Primary Care/Development Pediatrics
Careful and routine monitoring
Hearing Assessment
Visual Assessment
Monitoring of height, weight, and BMI
Otolaryngology (ENT)
Pediatric dentistry
Physiatrist/physical therapy
Psychiatric and Psychology
Psychiatric evaluation with a focus on autism spectrum disorder
Autism Diagnostic Observation Schedule (ADOS)
Cognitive or Developmental Assessment
Speech and Language Evaluation/Therapy
Adaptive Function Testing
Educational Assessment
Occupational Therapy
Neurology
motor development, coordination, and gait monitoring, as well as conditions that might be associated with hypotonia, like neuromuscular scoliosis and feeding problems
The true prevalence of PMS has not been determined. More than 1,200 people have been identified worldwide according to the Phelan–McDermid Syndrome Foundation.[65] However, it is believed to be underdiagnosed due to inadequate genetic testing and lack of specific clinical features. It is known to occur with equal frequency in males and females. Studies using chromosomal microarray for diagnosis indicate that at least 0.5% of cases of ASD can be explained by mutations or deletions in the SHANK3 gene.[58] In addition, when ASD is associated with ID, SHANK3 mutations or deletions have been found in up to 2% of individuals.[66][67]
The first case of PMS was described in 1985 by Watt et al., who described a 14-year-old boy with severe intellectual disability, mild dysmorphic features and absent speech, which was associated with terminal loss of the distal arm of chromosome 22.[68] In 1988, Phelan et al. described a similar clinical presentation associated with a de novo deletion in 22q13.3. Subsequent cases were described in the following years with a similar clinical presentation. Phelan et al. (2001), compared 37 subjects with 22q13 deletions with features of 24 cases described in the literature finding that the most common features were global developmental delay, absent or delayed speech and hypotonia. In 2001, Bonaglia et al.,[69] described a case that associated the 22q.13 deletion syndrome with a disruption of the SHANK3 gene (also called ProSAP2). The following year, Anderlid et al. (2002),[70] refined the area in 22q13 presumably responsible for the common phenotypic presentation of the syndrome to a 100kb in 22q13.3. Out of the three genes affected, SHANK3 was identified as the critical gene due to its expression pattern and function. Wilson et al.[71] (2003) evaluated 56 patients with the clinical presentation of PMS, all of whom had a functional loss of one copy of the SHANK3 gene. However, later the same group demonstrated that loss of SHANK3 gene was not an essential requirement for the disorder.[72]
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